FUS Transducer Research Articles

TFUSFormer: Physics-Guided Super-Resolution Transformer for Simulation of Transcranial Focused Ultrasound Propagation in Brain Stimulation.

Transcranial focused ultrasound (tFUS) has emerged as a new mode of non-invasive brain stimulation (NIBS), with its exquisite spatial precision and capacity to reach the deep regions of the brain. The placement of the acoustic focus onto the desired part of the brain is critical for successful tFUS procedures; however, acoustic wave propagation is severely affected by the skull, distorting the focal location/shape and the pressure level. High-resolution (HR) numerical simulation allows for monitoring of acoustic pressure within the skull but with a considerable computational burden. To address this challenge, we employed a 4× super-resolution (SR) Swin Transformer method to improve the precision of estimating tFUS acoustic pressure field, targeting operator-defined brain areas. The training datasets were obtained through numerical simulations at both ultra-low (2.0 [Formula: see text]) and high (0.5 [Formula: see text]) resolutions, conducted on in vivo CT images of 12 human skulls. Our multivariable datasets, which incorporate physical properties of the acoustic pressure field, wave velocity, and skull CT images, were utilized to train three-dimensional SR models. We found that our method yielded 87.99 ± 4.28% accuracy in terms of focal volume conformity under foreseen skull data, and accuracy of 82.32 ± 5.83% for unforeseen skulls, respectively. Moreover, a significant improvement of 99.4% in computational efficiency compared to the traditional 0.5 [Formula: see text] HR numerical simulation was shown. The presented technique, when adopted in guiding the placement of the FUS transducer to engage specific brain targets, holds great potential in enhancing the safety and effectiveness of tFUS therapy.

Modulation of cardio-respiratory activity in mice via transcranial focused ultrasound

Objective: The objective of this study was to investigate the effect of FUS on autonomic nervous system activity, including heart and respiratory rates, and to separate the thermal modulation from combined thermal and mechanical FUS effects.Methods: The thalamus and hypothalamus of wild-type mice were sonicated with a continuous-wave, 2 MHz FUS transducer at pressures of 425 and 850 kPa for 60 seconds. Cardiac and respiratory rates were monitored as signs of autonomic nervous activity. FUS-induced changes in autonomic activity were compared to FUS targeted to a spatially-distant motor region and to laser-induced heating.Results: FUS delivered to the primary target over the thalamus and hypothalamus at 850 kPa reversibly increased the respiratory rate by 6.5±3.2 breaths per minute and decreased the heart rate by 3.2±1.8 beats per minute. No significant changes occurred in this region at 425 kPa or when targeting the motor regions at 850 kPa. Laser heating with the same temperature rise profile produced by 850 kPa sonication resulted in cardiorespiratory modulation similar to that of FUS.Conclusions: FUS is capable of reversibly and non-invasively modulating cardiorespiratory activity in mice. Localized changes in temperature may constitute the main cause for this activity, though further investigation is warranted into the distinct and complementary mechanisms of mechanically- and thermally-induced FUS neuromodulation. Close monitoring of vital signs during FUS neuromodulation may be warranted to monitor systemic responses to stimulation.

DDEL-11. FOCUSED ULTRASOUND-MEDIATED DELIVERY OF ANTI-PROGRAMMED CELL DEATH-LIGAND 1 ANTIBODY TO THE BRAIN OF A PORCINE MODEL

Abstract Focused ultrasound-combined with microbubble-mediated blood-brain barrier opening (FUS-BBBO) has been established as a promising brain drug delivery technology for the treatment of brain tumors. Immune checkpoint inhibitor therapy is a form of cancer immunotherapy that has revolutionized the treatment of cancer and shown remarkable efficacy in a range of cancers. Previous studies reported successful delivery of a checkpoint inhibitor anti-PD-L1 antibody (aPD-L1) by FUS-BBBO in the mouse brain. The objective of this study was to evaluate the feasibility and safety of FUS-BBBO in the delivery of aDP-L1 to the brain of a large animal model. Pigs (4 weeks old, male, n=3) were used as the large animal model. A FUS transducer (frequency of 650 kHz, aperture of 65 mm, and a focal length of 65 mm) was used to sonicate three different brain regions in the presence of systemically injected microbubbles (Definity) for every pig. Near-infrared fluorescent dye-labeled aPD-L1 was injected intravenously to the pig after FUS sonication. Contrast-enhanced MRI was conducted to evaluate the BBB permeability. Pig brains were then harvested and imaged by the Licor Pear imaging system. Successful BBBO was confirmed by in vivo T1-weighted MR imaging. The average MR contrast enhancement volume in the FUS-targeted regions was 4.8× of that in the contralateral non-targeted regions. Ex vivo fluorescence imaging found that FUS sonication enhanced aPD-L1 delivery by 2.1× compared with the non-targeted regions. Histological analysis by hematoxylin and eosin (H&E) staining did not find evidence for tissue damage. These findings suggest that FUS-BBBO can achieve noninvasive, localized, and safe delivery of aPD-L1 to the brain of large animals, providing strong preclinical data to support the clinical translation of this promising technique for brain cancer immunotherapy.

Ultrasound-mediated blood–brain barrier opening uncovers an intracerebral perivenous fluid network in persons with Alzheimer’s disease

BackgroundFocused ultrasound (FUS)-mediated blood–brain barrier (BBB) opening is under investigation as a therapeutic modality for neurodegeneration, yet its effects in humans are incompletely understood. Here, we assessed physiologic responses to FUS administered in multifocal brain sites of persons with Alzheimer’s disease (AD).MethodsAt a tertiary neuroscience institute, eight participants with AD (mean age 65, 38% F) enrolled in a phase 2 clinical trial underwent three successive targeted BBB opening procedures at 2 week intervals using a 220 kHz FUS transducer in combination with systemically administered microbubbles. In all, 77 treatment sites were evaluated and encompassed hippocampal, frontal, and parietal brain regions. Post-FUS imaging changes, including susceptibility effects and spatiotemporal gadolinium-based contrast agent enhancement patterns, were analyzed using serial 3.0-Tesla MRI.ResultsPost-FUS MRI revealed expected intraparenchymal contrast extravasation due to BBB opening at all targeted brain sites. Immediately upon BBB opening, hyperconcentration of intravenously-administered contrast tracer was consistently observed around intracerebral veins. Following BBB closure, within 24–48 h of FUS intervention, permeabilization of intraparenchymal veins was observed and persisted for up to one week. Notably, extraparenchymal meningeal venous permeabilization and associated CSF effusions were also elicited and persisted up to 11 days post FUS treatment, prior to complete spontaneous resolution in all participants. Mild susceptibility effects were detected, however no overt intracranial hemorrhage or other serious adverse effects occurred in any participant.ConclusionsFUS-mediated BBB opening is safely and reproducibly achieved in multifocal brain regions of persons with AD. Post-FUS tracer enhancement phenomena suggest the existence of a brain-wide perivenous fluid efflux pathway in humans and demonstrate reactive physiological changes involving these conduit spaces in the delayed, subacute phase following BBB disruption. The delayed reactive venous and perivenous changes are consistent with a dynamic, zonal exudative response to upstream capillary manipulation. Further preclinical and clinical investigations of these FUS-related imaging phenomena and of intracerebral perivenous compartment changes are needed to elucidate physiology of this pathway as well as biological effects of FUS administered with and without adjuvant neurotherapeutics.Trial registration: ClinicalTrials.gov identifier: NCT03671889, registered 9/14/2018

Dynamics of focused ultrasound-enhanced glymphatic transportation in the mouse brain

The glymphatic system, a perivascular network in the brain, regulates the exchange of cerebrospinal fluid and interstitial fluid in the perivascular space. Focused ultrasound combined with microbubbles (FUSMB) has been recently shown feasible to manipulate the glymphatic transportation by enhancing the intranasal delivery of agents in the perivascular space. The objective of this study was to reveal the dynamics of FUSMB-enhanced agent transport in the glymphatic system. A ring-shaped FUS transducer was confocally aligned with an objective of a two-photon microscope (2PM). Fluorescently labeled albumin was administered to the mouse nose, where it transported along olfactory nerve and trigeminal nerve from nose to brain and then spread in perivascular space in the brain. FUS sonication was performed after intravenous injection of microbubbles. In vivo 2PM recorded the dynamics of agent transportation before, during, and after FUS sonication. Time-lapse recording showed that FUSMB enhanced the agent accumulation at the perivascular space. FUS significantly increased the accumulation of the agent in the perivascular space by 1.2-folds immediately after the sonication (p = 0.0325), and 1.6-folds at 5 min after the sonication (p < 0.0001). In conclusion, this study showed, for the first time, direct evidence of FUSMB-enhanced glymphatic transportation in the mouse brain.

Simple, inexpensive, and ergonomic phantom for quality assurance control of MRI guided Focused Ultrasound systems.

The popularity of Magnetic Resonance guided Focused Ultrasound (MRgFUS) as a beneficial therapeutic solution for many diseases is increasing rapidly, thus raising the need for reliable quality assurance (QA) phantoms for routine testing of MRgFUS systems. In this study, we propose a thin acrylic film as the cheapest and most easily accessible phantom for assessing the functionality of MRgFUS hardware and software. Through the paper, specific QA tests are detailed in the framework of evaluating an MRgFUS preclinical robotic device comprising a single element spherically focused transducer with a nominal frequency of 2.75MHz. These tests take advantage of the reflection of ultrasonic waves at a plastic-air interface, which results in almost immediate lesion formation on the film at a threshold of applied acoustic energy. The phantom offered qualitative information on the power field distribution of the FUS transducer and the ability to visualize different FUS protocols. It also enabled quick and reliable assessment of various navigation algorithms as they are used in real treatments, and also allowed for the assessment of the accuracy of robotic motion. Therefore, it could serve as a useful tool for detecting defects in system's performance over its lifetime after establishing a baseline while concurrently contributing to establish QA and calibration guidelines for clinical routine controls.

Deep Neural Network for Navigation of a Single-Element Transducer During Transcranial Focused Ultrasound Therapy: Proof of Concept.

Transcranial focused ultrasound (tFUS) has gained attention in the field of brain stimulation owing to its non-invasive neurotherapeutic potentials. However, complex interactions between acoustic waves and the cranium may introduce misalignment of the acoustic focus from a geometric target location, thus, necessitate on-site feedback of real-time navigational information of the transducer (spatial coordinates and angular orientation) for the operators to accurately place the acoustic focus to the desired brain area. In this study, we propose a deep-learning-based network model that can provide spatial navigational information of a single-element FUS transducer with respect to the targeted brain region. The training dataset were acquired through forward simulations that reflect the different tFUS transmissions for each skull structure using cranial computed tomography (CT) image data. The performance of the network was evaluated through three ex vivo calvaria. As a result show that the presented neural network-based method can an accurately navigate the FUS transducer with the conformity of ∼99.59% in placement of the transducer and ∼74.49% in the focal volume and an average difference of ∼0.96 mm in the focal point, all capable of real-time operation (∼10 ms).

Challenges regarding MR compatibility of an MRgFUS robotic system

Numerous challenges are faced when employing Magnetic Resonance guided Focused Ultrasound (MRgFUS) hardware in the Magnetic Resonance Imaging (MRI) setting. The current study aimed to provide insights on this topic through a series of experiments performed in the framework of evaluating the MRI compatibility of an MRgFUS robotic device. All experiments were performed in a 1.5 T MRI scanner. The main metric for MRI compatibility assessment was the signal to noise ratio (SNR). Measurements were carried out in a tissue mimicking phantom and freshly excised pork tissue under various activation states of the system. In the effort to minimize magnetic interference and image distortion, various set-up parameters were examined. Significant SNR degradation and image distortion occurred when the FUS transducer was activated mainly owing to FUS-induced target and coil vibrations and was getting worse as the output power was increased. Proper design and stable positioning of the imaged phantom play a critical role in reducing these vibrations. Moreover, isolation of the phantom from the imaging coil was proven essential for avoiding FUS-induced vibrations from being transferred to the coil during sonication and resulted in a more than 3-fold increase in SNR. The use of a multi-channel coil increased the SNR by up to 50 % compared to a single-channel coil. Placement of the electronics outside the coil detection area increased the SNR by about 65 %. A similar SNR improvement was observed when the encoders' counting pulses were deactivated. Overall, this study raises awareness about major challenges regarding operation of an MRgFUS system in the MRI environment and proposes simple measures that could mitigate the impact of noise sources so that the monitoring value of MR imaging in FUS applications is not compromised.

Passive and Doppler-based assessment of cavitation activity induced by pulsed focused ultrasound

Pulsed focused ultrasound (pFUS) exposures utilizing short, nonlinearly distorted pulses at low duty cycle have been shown to enhance drug and gene delivery to targeted tissue through inertial cavitation activity. Passive cavitation detection (PCD) and mapping of broadband emissions are current conventional methods to monitor and quantify cavitation but provide limited spatial resolution. Here, plane-wave Doppler imaging was used with PCD to quantify pFUS-induced cavitation in ex vivo bovine tissues and in vivo surgically exposed porcine liver, kidney, and pancreas. A 1.5 MHz FUS transducer (aperture 75 mm, F-number 0.75) was used to deliver 60 pulses (duration 1 ms, 0.1% duty cycle, focal pressure p+ = 70i–110 MPa, p− = 13–20 MPa). A coaxially mounted ATL P7-4 ultrasound imaging probe was used for PCD during the FUS pulse, and Doppler and B-mode sequences. Disrupted tissue areas were collected for histology and compared to Doppler power images. Maximum Doppler power was found to correlate to broadband noise level for each FUS pulse. The Doppler power map integrated over the exposure was observed to correlate spatially with tissue disruption area from histology, which thus represents a promising real-time metric for quantifying cavitation activity induced by pFUS exposures. [Work supported by NIH R01CA154451, R01EB025187, and R01EB23910.]

Differential evolution method to find optimal location of a single-element transducer for transcranial focused ultrasound therapy

Background and objectiveFocused ultrasound (FUS) has been receiving growing attention as a noninvasive brain stimulation tool because of its superior spatial specificity and depth penetrability. However, the large mismatch of acoustic properties between the skull and water can disrupt and shift the acoustic focus in the brain. In this paper, we present a numerical method to find the optimal location of a single-element FUS transducer, which creates focus on the target region. MethodsThe score function, representing the superposition of acoustic waves according to the relative phase difference and transmissibility, was defined based on time-reversal invariance of acoustic waves and depending on the spatial location of the transducer. The optimal location of the transducer was then determined using a differential evolution algorithm. To assess the proposed method, we conducted a forward simulation and compared the resulting focal location to the desired target point. We also performed experimental validation by measuring the acoustic pressure field through an ex vivo human skull in a water tank. ResultsThe numerical results indicated that the score function had a positive proportional relationship with the acoustic pressure at the target. Moreover, for the optimized transducer location, both the numerical and experimental results showed that the normalized acoustic pressure at the target was higher than 0.9. ConclusionsIn this study, we developed an optimization method to place a single-element transducer that effectively transmits acoustic energy to the targeted region in the brain. Our numerical and experimental results demonstrate that the proposed method can provide an optimal transducer location for safe and efficient FUS treatment.

Living Rat SSVEP Mapping With Acoustoelectric Brain Imaging.

Acoustoelectric Brain Imaging (ABI) is a potential method for mapping brain electrical activity with high spatial resolution (millimeter). To resolve the key issue for eventual realization of ABI, testing that recorded acoustoelectric (AE) signal can be used to decode intrinsic brain electrical activity, the experiment of living rat SSVEP measurement with ABI is implemented. A 1-MHz ultrasound transducer is focused on the visual cortex of anesthetized rat. With visual stimulus, the electroencephalogram and AE signal are simultaneously recorded with Pt electrode. Besides, with FUS transducer scanning at the visual cortex, corresponding AE signals at different spatial positions are decoded and imaged. Consistent with the directly measured SSVEP, decoded AE signal presents a clear event-related spectral perturbation (ERSP). And, decoded AE signal is of high amplitude response at the base and harmonics of the visual stimulus frequency. What's more, for timing signal, a significant positive amplitude correlation is observed between decoded AE signal and simultaneously measured SSVEP. In addition, the mean SNRs of SSVEP and decoded AE signal are both significantly higher than that of background EEG. Finally, with one fixed recording electrode, the active area with an inner diameter of 1mm is located within the 4 mm×4 mm measurement region. Experimental results demonstrate that the millimeter-level spatial resolution SSVEP measurement of living rat is achieved through ABI for the first time. This study confirms that ABI should shed light on high spatiotemporal resolution neuroimaging.

Affordable stereotactic-guided focused ultrasound device for tunable drug delivery to the mouse brain

Focused ultrasound combined with microbubble (FUS+MB)-mediated blood brain barrier (BBB) opening is not only a promising technique for clinical applications but also a powerful tool for preclinical neuroscience and neuro-oncology research. However, existing FUS systems are expensive and lack the flexibility of modulating BBB opening volume, which prevents a broader research community from adopting the FUS+MB technique in preclinical studies. To address the challenge, we developed a low cost (∼$100), mini FUS transducer with the capability to modulate BBB opening size that can be readily integrated with a standard stereotaxic frame for mouse. Specifically, we manufactured in-house mini FUS transducers with three frequencies (1.5, 3.0, and 6.0 MHz), and quantified BBB opening and targeting accuracy at varying pressures (0.20 to 0.81 MPa). The volume of FUS+MB-induced BBB opening was evaluated using both contrast-enhanced MRI and Evans blue extravasation. Our results showed that we can achieve varying amount of Evans blue delivery and BBB opening size by modulating the transducer frequency and acoustic pressure. Additionally, the amount of Evans blue delivery and BBB opening had a significant linear correlation with the cavitation index (defined by the ratio between acoustic pressure and frequency). We believe that this stereotaxic-guided FUS system will lower the barrier for adopting the FUS technique in a broader research community.

HGG-40. FOCUSED ULTRASOUND ENHANCES ETOPOSIDE DELIVERY IN A MURINE PONTINE GLIOMA MODEL

BackgroundDiffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brain cancer with limited treatment options and poor survival. The delivery of systemic therapies in this disease is severely limited by the blood-brain barrier (BBB). Focused ultrasound combined with intravenous microbubbles (FUS+MB) can effectively open the BBB permitting the entry of drugs across the cerebrovasculature. Etoposide is a chemotherapy frequently used in pediatric oncology with well-established anti-tumor effects but limited efficacy when administered systemically in DIPG. Given that FUS+MB in DIPG is not well studied, our goal was to determine the feasibility of ultrasound-mediated BBB opening and etoposide delivery in a preclinical murine pontine glioma model. MethodsA syngeneic, orthotopic model was established by stereotactic injection of PDGF-B+PTEN-/-p53-/- murine glioma cells into the pons of B6 albino mice. Mice were randomly divided into control (n=6) or FUS+MB groups (n=6). A single-element, spherical-segment FUS transducer (center frequency=1.5MHz) driven by a function generator through a power amplifier was used with concurrent microbubble injection to sonicate the tumor and its margins on post-injection day 14. Immediately after treatment, 5 mg/kg of intraperitoneal etoposide was administered to all 12 mice. All animals underwent cardiac puncture and blood sampling, followed by transcardiac perfusion and brain harvesting. Liquid chromatography-mass spectometry was performed on both serum and tumor tissue to measure etoposide levels. ResultsContrast-enhanced MRI demonstrated successful BBB opening in all FUS+MB mice. Compared to control (mean=20.98ng/g), etoposide concentration in the sonicated tumor tissue (mean=164.77ng/g) was nearly eight times greater. Lastly, the mean brain tumor–to-serum ratio was more than fivefold higher in the treated mice (1.50%) compared with the control mice (0.28%) (P<0.005). ConclusionsFUS+MB is hereby shown successful in BBB opening and enhanced delivery of etoposide in a preclinical pontine glioma model.

Beam characterization of a custom, handheld focused ultrasound system using thermochromic liquid crystal films

AbstractFocused Ultrasound (FUS) continues to gain acceptance in the clinical realm for its ability to provide effective, non‐invasive therapeutic treatments to almost any region of the body for a host of ablative and non‐ablative applications. The development of FUS devices and their implementation requires reliable characterization and quality assurance methods to verify acoustic pressure fields and focal region characteristics. The use of hydrophones is a conventional technique for mapping the acoustic field in 3 dimensions to provide focal dimensions and location. Hydrophones, however, are expensive and may be damaged even at relatively low acoustic amplitudes. Data collection with these devices can also be labor intensive and difficult to accurately reproduce. We present preliminary findings for the development of an alternative characterization process for FUS transducers that is relatively inexpensive and time efficient. Thermochromic liquid crystal (TLC) film sensors exploit the thermochromic effect, in which exposure to specific temperature changes cause a visible change in colour. The method was tested on a portable FUS system developed in‐house for FUS‐based therapeutic applications, comprised of a 3.57 MHz FUS transducer, and a custom‐fabricated coupling cone. The results demonstrated that this method using TLC films was able to accurately provide dimensions of the focal zone and its position relative to the transducer hardware. Numerical simulations were performed along with acoustic hydrophone measurements to corroborate this data, which were found to be in general agreement. With future refinements, this cost‐effective method could be practical as an expedient and cost‐effective characterization technique for in‐house FUS transducer development.

MR-guided focused ultrasound application for moving target tumor ablation in abdominal area: coil selection.

Magnetic Resonance Imaging (MRI)-guided Focused Ultrasound Surgery (MRgFUS) is a non-invasive thermal ablation method utilizing high-intensity focused ultrasound (HI-FU) energy for tissue ablation under MRI with real-time thermal mapping. Ablating to a dynamic target as in the liver is very challenging, requiring approval. A novel quality-assured liver tumor ablation system has been proposed for clinics. The paper reports the evaluation of conventional and new MR-receiving coils. To evaluate the suitability of MR coils as part of the MRgFUS treatment system for liver, while simulating breathing motion in pre-clinical settings. The novel software communicates with the MR scanner and the transducer. To monitor the temperature via proton resonance frequency (PRF) methodology echo planar imaging (EPI) sequence was used while the algorithms of static, static and dynamic tracking were tested with sonications of 100 W for 30 s on tissue-mimicking phantoms. Different coil sets were used to assess the performance of the system for fitness for dynamic thermometry. Finally, in vivo experiments were performed over a porcine model. Single-loop four-channel Duoflex and Gem coils provided adequate signal-to-noise ratio and contrast with consistent thermal readings. Body array coils showed severe loss of signal in dynamic cases since the integration of tracking algorithm causes low efficiency. Body array coils are unsuitable for MRgFUS of the liver due to signal loss. The dedicated coil set with a single loop around the FUS transducer combined with four-channel arrays might be the best option for liver treatment using dynamic MRgFUS applications.

MR thermometry-guided ultrasound hyperthermia of user-defined regions using the ExAblate prostate ablation array

BackgroundHyperthermia therapy (HT) has shown to be an effective adjuvant to radiation, chemotherapy, and immunotherapy. In order to be safe and effective, delivery of HT requires maintenance of target tissue temperature within a narrow range (40–44 °C) for 30–60 min, which necessitates conformal heat delivery and accurate temperature monitoring. The goal of this project was to develop an MR thermometry-guided hyperthermia delivery platform based upon the ExAblate prostate array that would achieve uniform stable heating over large volumes within the prostate, while allowing the user to precisely control the power deposition patterns and shape of the region of treatment (ROT).MethodsThe HT platform incorporates an accelerated multi-slice real time MR thermometry pulse sequence and reconstruction pipeline. Temperature uniformity over a large contiguous area was achieved by multi-point temperature sampling with multi-focal feedback power control. The hyperthermia delivery system was based on an InSightec ExAblate 2100 prostate focused ultrasound ablation system, and HeartVista’s RTHawk real-time MRI system integrated with a 3 T MRI scanner. The integrated system was evaluated in experiments with a tissue-mimicking phantom for prolonged exposures with a target temperature increase of 7 °C from baseline.ResultsFive various shapes of the region of treatment, defined on a 5 × 5 grid (35 × 35 mm, 11–25 focal spots per shape), were implemented to evaluate the performance of the system. MR temperature images, acquired after steady state was reached, showed different patterns of heating that closely matched the prescribed regions. Temperature uncertainty of the thermometry acquisition was 0.5 °C. The time to reach the target temperature (2:58–7:44 min) depended on the chosen ROT shape and on the distance from transducer to focal plane. Pre-cooling with circulating water helped to reduce near-field heating.ConclusionsWe have implemented a real-time MR thermometry-guided system for hyperthermia delivery within user-defined regions with the ExAblate prostate array and evaluated it in phantom experiments for different shapes and focal depths. Our results demonstrate the feasibility of using a commercially available endorectal FUS transducer to perform spatially-conformal hyperthermia therapy and could lead to a new set of exciting applications for these devices.

A focused ultrasound treatment system for moving targets (part I): generic system design and in-silico first-stage evaluation

BackgroundFocused ultrasound (FUS) is entering clinical routine as a treatment option. Currently, no clinically available FUS treatment system features automated respiratory motion compensation. The required quality standards make developing such a system challenging.MethodsA novel FUS treatment system with motion compensation is described, developed with the goal of clinical use. The system comprises a clinically available MR device and FUS transducer system. The controller is very generic and could use any suitable MR or FUS device. MR image sequences (echo planar imaging) are acquired for both motion observation and thermometry. Based on anatomical feature tracking, motion predictions are estimated to compensate for processing delays. FUS control parameters are computed repeatedly and sent to the hardware to steer the focus to the (estimated) target position. All involved calculations produce individually known errors, yet their impact on therapy outcome is unclear. This is solved by defining an intuitive quality measure that compares the achieved temperature to the static scenario, resulting in an overall efficiency with respect to temperature rise. To allow for extensive testing of the system over wide ranges of parameters and algorithmic choices, we replace the actual MR and FUS devices by a virtual system. It emulates the hardware and, using numerical simulations of FUS during motion, predicts the local temperature rise in the tissue resulting from the controls it receives.ResultsWith a clinically available monitoring image rate of 6.67 Hz and 20 FUS control updates per second, normal respiratory motion is estimated to be compensable with an estimated efficiency of 80%. This reduces to about 70% for motion scaled by 1.5. Extensive testing (6347 simulated sonications) over wide ranges of parameters shows that the main source of error is the temporal motion prediction. A history-based motion prediction method performs better than a simple linear extrapolator.ConclusionsThe estimated efficiency of the new treatment system is already suited for clinical applications. The simulation-based in-silico testing as a first-stage validation reduces the efforts of real-world testing. Due to the extensible modular design, the described approach might lead to faster translations from research to clinical practice.

Open-source, small-animal magnetic resonance-guided focused ultrasound system.

BackgroundMR-guided focused ultrasound or high-intensity focused ultrasound (MRgFUS/MRgHIFU) is a non-invasive therapeutic modality with many potential applications in areas such as cancer therapy, drug delivery, and blood-brain barrier opening. However, the large financial costs involved in developing preclinical MRgFUS systems represent a barrier to research groups interested in developing new techniques and applications. We aim to mitigate these challenges by detailing a validated, open-source preclinical MRgFUS system capable of delivering thermal and mechanical FUS in a quantifiable and repeatable manner under real-time MRI guidance.MethodsA hardware and software package was developed that includes closed-loop feedback controlled thermometry code and CAD drawings for a therapy table designed for a preclinical MRI scanner. For thermal treatments, the modular software uses a proportional integral derivative controller to maintain a precise focal temperature rise in the target given input from MR phase images obtained concurrently. The software computes the required voltage output and transmits it to a FUS transducer that is embedded in the delivery table within the magnet bore. The delivery table holds the FUS transducer, a small animal and its monitoring equipment, and a transmit/receive RF coil. The transducer is coupled to the animal via a water bath and is translatable in two dimensions from outside the magnet. The transducer is driven by a waveform generator and amplifier controlled by real-time software in Matlab. MR acoustic radiation force imaging is also implemented to confirm the position of the focus for mechanical and thermal treatments.ResultsThe system was validated in tissue-mimicking phantoms and in vivo during murine tumor hyperthermia treatments. Sonications were successfully controlled over a range of temperatures and thermal doses for up to 20 min with minimal temperature overshoot. MR thermometry was validated with an optical temperature probe, and focus visualization was achieved with acoustic radiation force imaging.ConclusionsWe developed an MRgFUS platform for small-animal treatments that robustly delivers accurate, precise, and controllable sonications over extended time periods. This system is an open source and could increase the availability of low-cost small-animal systems to interdisciplinary researchers seeking to develop new MRgFUS applications and technology.

Neuronavigation-Guided Focused Ultrasound-Induced Blood-Brain Barrier Opening: A Preliminary Study in Swine

FUS-induced BBB opening is a promising technique for noninvasive and local delivery of drugs into the brain. Here we propose the novel use of a neuronavigation system to guide the FUS-induced BBB opening procedure and investigate its feasibility in vivo in large animals. We developed an interface between the neuronavigator and FUS to allow guidance of the focal energy produced by the FUS transducer. The system was tested in 29 swine by more than 40 sonication procedures and evaluated by MR imaging. Gd-DTPA concentration was quantitated in vivo by MR imaging R1 relaxometry and compared with ICP-OES assay. Brain histology after FUS exposure was investigated using H&E and TUNEL staining. Neuronavigation could successfully guide the focal beam, with precision comparable to neurosurgical stereotactic procedures (2.3 ± 0.9 mm). A FUS pressure of 0.43 MPa resulted in consistent BBB opening. Neuronavigation-guided BBB opening increased Gd-DTPA deposition by up to 1.83 mmol/L (a 140% increase). MR relaxometry demonstrated high correlation with ICP-OES measurements (r(2) = 0.822), suggesting that Gd-DTPA deposition can be directly measured by imaging. Neuronavigation provides sufficient precision for guiding FUS to temporally and locally open the BBB. Gd-DTPA deposition in the brain can be quantified by MR relaxometry, providing a potential tool for the in vivo quantification of therapeutic agents in CNS disease treatment.

Optimal Imaging of In Vitro Clot Sonothrombolysis by MR‐Guided Focused Ultrasound

As magnetic resonance-guided focused ultrasound (MRgFUS) sonothrombolysis relies on mechanical rather than thermal mechanisms to achieve clot lysis, thermometry is not useful for the intraoperative monitoring of clot breakdown by MRgFUS. Therefore, the purpose of this study was to evaluate the optimum imaging sequence for sonothrombolysis. In vitro blood drawn from 6 healthy volunteers was imaged using T1, T2 spin-echo, and T2 gradient-echo (GRE) sequences both before and after sonication using an Insightec ExAblate 4000 FUS transducer. Signal intensities of the three MR imaging sequences were measured and normalized to background signal for each time point. Representative samples of the pre- and postsonication clot were also sent to pathology for hematologic analysis. After sonication, the clot in the treatment tube was fully lysed as evidenced by physical and hematologic evaluation. The difference between pre- and postsonicated normalized signal intensity ratios demonstrated statistical significance only on T2 and GRE sequences (P < .001). However, significant blooming artifact limited interpretation on all GRE images. T2 is the most appropriate sequence for the evaluation of mechanical MRgFUS sonothrombolysis of an in vitro clot. These findings are consistent across the oxidative states of clot up to 48 hours.